Title of project

The PAS domain of Kv11.1: Have we PASsed on a novel cardiac-safe therapeutic target in type 2 diabetes?

Abstract

β Cell secretory failure is a key cause of type 2 diabetes (T2D), and thus a critical therapeutic target. The K+ channel K_v11.1, well-known for its role in cardiomyocyte repolarization, has been implicated in insulin secretion. Loss-of-function mutations in K_v11.1 lead to long QT syndrome (LQT), characterized by risk of ventricular arrhythmia and sudden cardiac death. Interestingly, some, but not all, of these mutations also cause insulin hypersecretion, yet K_v11.1 remains unexplored as a drug target in T2D due to anticipated cardiac adverse effects of manipulating K+ conductance. However, exciting reanalysis of clinical data by our lab suggests that K_v11.1 is involved in insulin secretion, not through its K+ conducting properties, but through its intracellular N-terminal Per-Arnt-Sim (PAS) domain. PAS domains mediate interaction with other proteins, and thus, K_v11.1’s PAS domain may regulate insulin secretion by interacting with proteins of the exocytotic machinery. This notion also raises the intriguing possibility that K_v11.1 has ion-current-unrelated functions in cardiomyocytes as well. This is in line with data showing multiple proteins interacting with K_v11.1’s N-terminal domain in the heart. We therefore hypothesize that K_v11.1, unrelated to conducting K+, regulates insulin secretion in β cells and serves alternative functions in cardiomyocytes by interacting with other proteins through its PAS domain. Our aims are to 1. identify binding partners of K_v11.1’s PAS domain in β cells and cardiomyocytes, 2. investigate if insulin secretion and relevant cardiac functions are regulated by the PAS domain, and 3. translate our findings to the human setting. To do this, we will backtranslate the clinical LQT data into CRISPR Cas9 gene-edited murine and human cardiomyocyte and β cell lines and perform unbiased proteomic and interactome analyses, conduct targeted functional experiments in these cell lines, and further explore the link between LQT and glycemic phenotypes in large human databases. The perspective of this study is to add a new and original angle on our understanding of K_v11.1 in the heart and underline the PAS domain as a new cardiacsafe therapeutic target in T2D.